Singlet oxygen plays a central role in many applications, such as photodynamic inactivation of microorganisms, photodynamic therapy of cancers, photoinduced oxidation, photodegradation of polymers, wastewater treatment, and fine chemical synthesis. Photodynamic inactivation (PDI) of bacteria has become an emerging and evolving strategy against infectious diseases, especially those related to multidrug resistance, because microorganisms do not appear to readily develop resistance toward PDI. In this regard, multidrug-resistant bacterial strains are shown to be killed by PDI as easily as their naïve counterparts. During PDI and when the level of the reactive oxygen species (ROS) produced exceeds bacterial detoxification and repair capabilities, the ROS can damage intracellular DNA, RNA, proteins, lipids, and cytoplasmic membrane, which leads to bacteria death.
Gram-positive and Gram-negative bacteria differ in membrane permeability due to the difference in the outer membrane structures. Gram-positive bacteria can easily take up most neutral or anionic photosensitizers and be readily photoinactivated, which is not the case for Gram-negative bacteria. This difference has led the development of photosensitizers toward polycationic conjugates or cationic photosensitizers to facilitate uptake by the bacterial cells. Importantly, some studies have shown that singlet oxygen, when produced sufficiently close to the bacteria, can diffuse into the bacteria cells causing fatal damage to the cells. Accordingly, photosensitizers with enhanced singlet oxygen production efficiency are highly desired, regardless of their charge properties.
The ground electronic state of molecular oxygen is a spin triplet. Ground-state (triplet) oxygen is not very reactive. However, triplet oxygen can be activated by the addition of energy and transformed into reactive oxygen species. The two electronically excited singlet states are O2 (1Δg) and O2 (1Σg+), at 94 and 157 kJ/mol above the ground state, respectively. The O2 (1Σg+) state has a rather short lifetime, due to the spin-allowed transition to the O2 (1Δg) state. The O2 (1Δg) state is commonly referred to as singlet oxygen. Singlet oxygen has a relatively long lifetime (e.g. 10−6 to 10−3 seconds in solution) because of the spin-forbidden transition to the triplet state O2 (3Σg−). Singlet oxygen can be observed experimentally in the absorption and emission at about 1270 nm.
The most convenient method of singlet oxygen production is the photosensitization of sensitizing molecules in the presence of light and oxygen. Great progress has been made in identifying, designing and synthesizing molecules as efficient photosensitizers. Even noble metal nanostructures have demonstrated the capability of singlet oxygen production. Still, the ability of noble metal nanostructures to enhance the production of singlet oxygen has remained largely unexploited. Since singlet oxygen plays a very important role in cell damage, an abundant supply of singlet oxygen is required.
Photodynamic inactivation of bacteria, among other applications that utilize singlet oxygen, is currently limited by the insufficient generation of singlet oxygen while reacting with biological targets. Accordingly, improved compositions and methods of producing singlet oxygen are needed to address the shortcomings of existing methods. More particularly, new compositions and methods are needed that increase the efficiency of the production of singlet oxygen.
Fungi are a large group of eukaryotic organisms distantly related to mammals, yet with similarities in the plasma membrane to that of mammalian cells. Most fungi have a rigid cell membrane including polysaccharides, such as chitin and ergosterol, whereas in mammalian cell membranes ergosterol is replaced by cholesterol. The similarities that exist between fungal and mammalian cell membranes render it challenging to develop antifungal drugs with low toxicity to humans.
Tricophyton rubrum, herein T. rubrum, is a dermatophytic fungus that commonly causes nail, skin and hair infections, i.e. dermatophytoses, due to its ability to utilize keratin. Fungal nail infection is the most common T. rubrum infection in humans worldwide, affecting 2%-13% of the world population. T. rubrum infections have indeed become a global phenomenon.
Fungal nail infection may be caused by a number of reasons, including less hygienic lifestyles, contact with infected skin scales, or contact with the fungi in wet areas such as swimming pools, showers and locker rooms. Infected patients may experience embarrassment in social and work situations, and carry the danger of transmitting the infection to others. Patients with diabetes, weakened immune system due to diseases such as HIV, and patients undergoing nail surgeries or cancer therapy, are highly susceptible to fungal nail infections, which could be serious, even fatal.
One drawback of existing drugs used to treat fungal infections is the relatively long-term treatments (some requiring up to 18 months to cure), and adverse side effects such as liver damage or drug interactions. Furthermore, the lack of targeted delivery of drugs may lead to less effective cure, as evidenced by slow and incomplete clearance of the infections. While molecular photosensitizers, such as methylene blue, toluidine blue, protoporphyrin and hematoporphyrin, have been shown to treat T. rubrum infections noninvasively, the use of molecular photosensitizers in PDI suffers from the drawback that most of the photosensitizers are highly hydrophobic and tend to aggregate in aqueous media, which reduces the efficiency of ROS generation and thus the efficacy of PDI.
Device-based treatments for fungal infections, such as laser treatments, iontophoresis, ultrasound treatments and photodynamic therapy, have been reported with varying degrees of success. So far, only laser treatments for cosmetic uses are FDA-approved. However, more studies are needed to validate the technique. The use of ultrasound devices has been investigated using a canine nail model. Still, the device itself seems complicated, and further studies will be required to assess it as a modality of antifungal treatment. Therefore, there is an ongoing need for noninvasive and user-friendly methods for treating of fungal infections.